【Circ Genom Precis Med】百萬退伍軍人項目中與家族性高膽固醇血症相關的遺傳變異對LDL-C水平……(附原文)

Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran ProgramCirc Genom Precis Med research-article 
Dec 01, 2018: 11 (12), e002192
10.1161/CIRCGEN.118.002192
Background:Familial hypercholesterolemia (FH) is characterized by inherited high levels of LDL-C (low-density lipoprotein cholesterol) and premature coronary heart disease. Over a thousand low-frequency variants in LDLR, APOB, and PCSK9 have been implicated in FH, but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331 107 multiethnic participants.家族性高膽固醇血症（FH）的特點是遺傳性低密度脂蛋白膽固醇（LDL-C）高水平和早發冠心病。LDLR、APOB和PCSK9中超過1000個低頻變異與FH相關，但在人群水平上鮮有檢測。我們旨在評估331,107例多民族參與者中FH變異子集對LDL-C和臨床終點的表型效應。Methods:We examined the individual and collective association between putatively pathogenic FH variants included on the Million Veteran Program biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters.我們探討了包括在百萬退伍軍人項目生物庫陣列中的推測致病性FH變體與15年間最大LDL-C水平（maxLDL）之間的個體和集體關聯。我們利用來自6170萬次臨床就醫的數據評估了對臨床終點的集體效應。Results:We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4–80.2 mg/dL). Phenotypic effects were similar for European Americans and African Americans, despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL; P=1.2×10–152), and higher prevalence of clinical diagnoses related to hypercholesterolemia and coronary heart disease in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of coronary heart disease (odds ratio, 1.59; 95% CI, 1.36–1.86, P=1.1×10–8) but not peripheral artery disease.我們發現，在16個推測致病性FH變異（有≥30個觀察到的攜帶者），8個與maxLDL升高顯著相關（9.4-80.2 mg/dL）。歐洲裔美國人和非洲裔美國人儘管攜帶頻率有很大差異，但表型效應相似。基於對maxLDL的觀察結果，我們共識別了748名maxLDL（36.5±1.4 mg/dL；P=1.2×10-152）升高的攜帶者（1：443），並且在全表型組掃描中高膽固醇血症和冠心病相關的臨床診斷率較高。校正maxLDL後，FH變異總體上與冠心病患病率較高相關（OR，1.59；95%CI，1.36-1.86，P=1.1×10-8），但與外周動脈疾病不相關。Conclusions:The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multiethnic populations is needed to accurately infer at-risk individuals from genetic screening.在變異體內和跨變異體之間，推測致病性FH變異的分布和表型效應具有異質性。在多民族人群中，FH變異的基因型-表型關聯需要更有力的證據來根據遺傳篩選準確識別高危個體。Footnotes

*A list of Members of VA Million Veteran Program are listed in the Appendix.Guest Editor for this article is Christopher Semsarian, MBBS, PhD, MPH.The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.118.002192.Yan V. Sun, PhD, MS, Department of Epidemiology, Emory University Rollins, School of Public Health, 1518 Clifton Rd. NE, Atlanta, GA 30322, email yan.v.******eduPeter W.F. Wilson, MD, Atlanta VA Medical Center, Emory Clinical Cardiovascular Research Institute, 1670 Clairmont Rd, Decatur, Atlanta, GA 30033, email peter.******gov

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Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran ProgramCirc Genom Precis Med research-article 
Dec 01, 2018: 11 (12), e002192
10.1161/CIRCGEN.118.002192